Research led by Washington University in St. Louis carried out in animals shows that restoring the activity of microglial cells in the brain could be a new treatment strategy for Alzheimer’s disease.
Approximately 5.8 million people in the United States have Alzheimer’s disease or related dementias. Treatments for the condition are limited, although the approval of an antibody treatment for early Alzheimer’s last year has led to new hope and increased activity by drug developers hoping to bring new treatments to patients.
Microglia are immune cells in the brain that respond to infections and damage and dispose of unwanted pathogens and accumulated waste proteins such as the amyloid beta proteins that accumulate in the brains of people with Alzheimer’s.
Writing in the journal Science Translational Medicine, Marco Colonna, a professor at Washington University School of Medicine in St. Louis, and colleagues discovered that microglia associated with amyloid beta plaques in patients with Alzheimer’s disease have high levels of human leukocyte Ig-like receptor B4 (LILRB4), which appears to suppress their beneficial activity.
Using a transgenic mouse model of Alzheimer’s disease, the researchers also saw considerable accumulation of LILRB4 in the microglia of the mice. They also found that LILRB4 binds to apolipoprotein E, which is linked to Alzheimer’s disease as certain genetic subtypes increase or decrease risk for developing the neurodegenerative condition.
However, when they treated the mice with an antibody targeting LILRB4, the amount of amyloid beta accumulation decreased, some behavioral abnormalities (the equivalent of dementia symptoms in humans) resolved, microglia protein clearing activity increased, and the expression of genes associated with interferon was reduced.
Previous research has shown links between other leukocyte Ig-like receptor proteins and neurodegeneration. However, the role LILRB4 and the microglia played in neurodegenerative disease pathology was previously unclear.
“LILRB2… was found to bind amyloid beta, and its mouse homolog, PIRB, was shown to contribute to Alzheimer’s disease neuropathology, suggesting that blockade of LILRB2 function may be therapeutically beneficial,” write the authors.
“Moreover, genetic studies have found DNA polymorphisms within the LILRB2 and LILRA2 genes associated with Alzheimer’s disease and amyotrophic lateral sclerosis, respectively, corroborating a link between the LILR region and susceptibility to neurodegeneration.”
This research is at an early stage and has yet to be translated to humans, but Colonna and colleagues hope it may lead to the development of a new treatment for Alzheimer’s disease in the future.
“Targeting activating or inhibitory receptors may yield different activation states. Future studies are needed to define similarities and differences in the signaling pathways elicited by these different strategies,” write the authors.
